The present invention relates to a synthetic route for producing various imidazopyridine derivatives, to certain intermediates useful therein, and to highly pure compounds produced thereby.
Imidazopyridines of the formula (1) are described in U.S. Pat. No. 4,382,938 as useful pharmaceutical agents. ##STR2##
Y is hydrogen, halogen, or C.sub.1 -C.sub.4 alkyl and X.sub.1 and X.sub.2 are independently a hydrogen, halogen, C.sub.1 -C.sub.4 alkoxy, C.sub.1 -C.sub.6 alkyl, CF.sub.3, CH.sub.2 S, CH.sub.3 SO.sub.2 or NO.sub.2. R.sub.1 and R.sub.2 are independently hydrogen, C.sub.1 -C.sub.5 alkyl, which may be substituted with, inter alia, halogen, hydroxy, etc., or together they form a heterocyclic ring. The compounds of formula (I) include the commercial product zolpidem which is sold in the hemitartrate form under the brand names Stilnox, Stilnoct, and Ambien. Zolpidem has the following formula. ##STR3##
The method disclosed in the above-cited patent for making the compounds of formula (I) can be outlined as follows: ##STR4##
The nitrile compound is converted to the primary amide compound by conventional methods and then the amide is saponified to form the acid compound. The acid compound can be converted to the final tertiary amide by known techniques including a reaction with an amine of the formula HNR.sub.1 R.sub.2 in the presence of carbonyldiimidazole or by forming the chloride of the acid and then reacting with amine of the formula HNR.sub.1 R.sub.2.
This process suffers from several drawbacks, especially from the commercial point of view. For example, the starting nitrile must be formed from the corresponding imidazopyridine compound (unsubstituted in the 3 position) which adds additional synthetic steps. Moreover, the use of toxic reactants such as potassium cyanide are required. A shorter reaction scheme that avoids the use of highly toxic reagents would be advantageous.
An improved synthesis scheme, as shown below, is disclosed in U.S. Pat. No. 4,794,185. ##STR5##
The above process is believed to correspond to the commercial process presently used for the production of zolpidem. The process is described in the patent as providing high yield with "excellent purity, after work up." While the number of steps has been reduced over the earlier process and the use of potassium cyanide can be avoided, the process uses special reactants, specifically the compounds of formula (III). Moreover, the replacement of the hydroxyl group with a chloride to form the compound of formula (V) and its subsequent removal means that chloride is a potentially troubling impurity in the final product. In addition, chlorination agents such as thionylchloride are highly hazardous compounds; making this synthetic scheme potentially dangerous to the operators and the environment. It would be desirable to have a process that could use inexpensive and safe reactants and that could form the free base of the final compound with very high purity.
Additional methods for making various imidazopyridines are disclosed by Schmitt et al., Aust. J. Chem., 1997, 50, 719-725. Among them is the reaction of certain 2-phenylimidazo[1,2-a]pyridines with freshly distilled ethyl glyoxylate to form ethyl 2-hydroxy-2-(2'-phenylimidazo[1,2-a]pyridin-3'-yl) acetate. This compound is reduced by adding phosphorous tetraiodide in dichloromethane to form ethyl 2-(2'-phenylimidazo[1,2-a]pyridin-3'-yl) acetate. Regarding such a procedure, Schmitt et al. states "The foregoing method of preparing the 2-hydroxyacetate and its conversion into the acetate may provide a convenient synthesis of the relevant intermediates for the preparation of alpidem and zolpidem."
Exactly what the alpidem or zolpidem intermediates would be and how they would be used (the intended synthesis scheme) is not explained. Indeed, it is not possible to directly convert the ester compounds of Schmitt et al. to the desired amide using conventional amidation techniques. Moreover, the use of ethyl glyoxylate is not convenient for a commercial scale production. Such a product is commercially sold, apparently exclusively, as a 50% toluene solution. In such a solution, a portion of the ethyl glyoxylate exists in a partly polymerized, and thus unreactive, form. De-polymerization can be carried out by heating. This appears to explain the need to use freshly distilled ethyl glyoxylate as taught in Schmitt et al. Besides the impracticability of using ethyl glyoxylate, the only disclosed reducing agent, phosphorous tetraiodide, is expensive, not readily available, and produces iodine- and phosphorous-containing wastes. Furthermore, Schmitt et al. teaches the isolation of the intermediates by column chromatography. These reactants and procedures are not convenient for scale up to a commercial size production.
Accordingly, it would be desirable to have a process that can use inexpensive and/or readily available reactants. It would also be desirable to have a process that can be readily scaled up, that does not require special purification techniques and that can produce a highly pure product.